Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:17][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[N:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(CCCCC(=O)O)nc1
Solvent: c1ccncc1
Product: O=C(O)CCCCc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cn1
Reaction time: 18 h
Yield: 63.7 %

Procedure:
4-Chlorobenzenesulphonyl chloride (1.09 g, 5.15 mmole) was added portionwise over 10 minutes to a solution of 5-(5-aminopyrid-2-yl)pentanoic acid (1.00 g, 5.15 mmole) in pyridine (15 ml). The resulting solution was stirred for 18 hours when the solvent was removed and the residue was dissolved in dilute sodium hydroxide solution (30 ml). This solution was extracted with ethyl acetate (4×50 ml) the extracts being discarded. The aqueous layer was acidified (pH 3) and extracted with ethyl acetate (4×100 ml). The combined ethyl acetate extracts were dried over magnesium sulphate, evaporated to dryness and the residue was recrystallised from acetonitrile to give the title compound (1.21 g) as a pale yellow solid. m.p. 145°-147° C.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:7][CH2:8][C:9]([O:11]C)=[O:10])[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].CO.C1COCC1>O>[C:9]([CH2:8][CH2:7][C:2]([CH3:13])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])([OH:11])=[O:10]
Reactant: COC(=O)CCC(C)(C)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)C(C)(C)CCC(=O)O

Procedure:
The diester from Step 1 (13.0 g), K2CO3 (19.1 g), MeOH (120 mL), THF (80 mL) and H2O (80 mL) were stirred at room temperature for 2 days. The organic solvent was removed in vacuo, the residue poured onto H2O and extracted twice with EtOAc. The aqueous layer was acidified with 3N HCl and extracted with EtOAc (3×). This organic phase was then washed with brine, dried and evaporated to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[CH3:73][N:74]([CH3:79])[CH2:75][CH2:76][CH2:77]O>C1COCC1>[CH3:73][N:74]([CH3:79])[CH2:75][CH2:76][CH2:77][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CN(C)CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 38.7 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.102 g, 0.221 mmol) was dissolved in THF (5.1 mL), and the solution was treated with triphenylphosphine (0.116 g, 0.442 mmol), 40% DEAD-toluene solution (0.201 mL, 0.442 mmol) and 3-(dimethylamino)propanol (0.130 mL, 1.10 mmol), followed by purification by flash column chromatography (chloroform/methanol=4/1) to obtain 4-[3-(dimethylamino)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0467 g, yield 39%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([OH:15])=O.BrC1C=CSC=1C(Cl)=O.Cl.[CH3:26][NH:27][O:28][CH3:29].C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[CH3:29][O:28][N:27]([CH3:26])[C:13]([C:9]1[S:10][CH:11]=[CH:12][C:8]=1[Br:7])=[O:15]
Reactant: CNOC
Reactant: O=C(O)c1sccc1Br
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1sccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1sccc1Br
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Oxalyl chloride (0.601 mL, 6.99 mmol, 1.2 eq) is added to a mixture of 3-bromothiophene-2-carboxylic acid (1.20 g, 5.80 mmol), N,N-dimethylformamide (several drops, catalytic amount), and anhydrous dichloromethane (25 mL) at ambient temperature under nitrogen over 20 minutes. The reaction is stirred for 17 hours, purged with nitrogen, and concentrated under reduced pressure to afford a tan solid. The crude 3-bromothiophene-2-carbonyl chloride is dissolved in dichloromethane (25 mL) and added dropwise, over 10 minutes, to a 0° C. solution of N,O-dimethylhydroxylamine hydrochloride (843 mg, 8.64 mmol), diisopropylethylamine (2.50 mL, 14.3 mmol), and dichloromethane (25 mL). The reaction is allowed to gradually warm to ambient temperature overnight. The reaction is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product is purified by chromatography on silica, eluting with 1:1 ethyl acetate/heptane, to give 3-bromo-thiophene-2-carboxylic acid methoxy-methyl-amide, as a white solid: TLC Rƒ0.33 (silica, 1:1 ethyl acetate/heptane); LC/MS: (M+H 249.94, RT=2.18 minutes); 1H NMR [(CD3)2SO), 300 MHz]: δ 7.85 (d, 1H, J=5.3 Hz), 7.17 (d, 1H, 5.3 Hz), 3.62 (s, 3H), 3.24 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26])(O)=[O:2].Cl.C([N:31]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:15][CH3:16])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:17][C:18](=[O:27])[C:19]1[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=1[Cl:25])(=[O:2])[NH2:31]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOc1c(C(=O)O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C(N)=O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a solution of 3-carboxy-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (153 mg) in dimethylformamide were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (109 mg) and 1-hydroxybenzotriazole (76.5 mg), and the mixture was stirred for 2 hours at ambient temperature. To the mixture was added conc. ammonia solution (0.2 ml) with stirring, and the mixture was stirred for 6 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethanol to give 3-carbamoyl-8-(2,6-dichlorobenzoylamino)-4-ethoxyquinoline (128.3 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][CH:3]=1.C([NH2:13])=O.C(O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: NC=O
Solvent: O=CO
Solvent: O
Product: CC(N)c1ccc(Cl)cc1
Temperature: 180 °C

Procedure:
A mixture of 4'-chloroacetophenone (103.3 g), formamide (98%; 123 g) and formic acid (97%; 8.3 ml) was stirred and heated at 180° C. The water produced in the reaction was removed by distillation together with some of the starting acetophenone which was separated and returned to the reaction vessel. Formic acid (70 ml total) was added in small aliquots over 8 hours. The reaction mixture was cooled and exhaustively extracted with toluene. The combined toluene extracts were washed with water, dried, filtered and the filtrate evaporated. Concentrated hydrochloric acid (70 ml) was added to the residue and the mixture boiled under reflux for 1 hour. The mixture was cooled, extracted with toluene and the aqueous layer basified with aqueous sodium hydroxide (5M). The solution was steam distilled until 1.4 1 of distillate had been collected and the distillate was extracted with ethyl acetate. The combined ethyl acetate extracts were dried, filtered and the filtrate evaporated to give an oil which was distilled to give (±)-1-(4-chlorophenyl)ethylamine, b.p. 120°-122° C. (19 mmHg). A small portion of the distillate was dissolved in dry ether and an equal volume of saturated ethereal hydrogen chloride was added. The solid formed was collected by filtration and dried to give (±)-1-(4-chlorophenyl)ethylamine hydrochloride, m.p. 186°-189° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]3[N:24]=[N:25][N:26]=[C:16]3[C:15]=2[NH2:27])[CH:2]=1.[C:28](OC)(OC)(OC)[CH2:29][CH2:30][CH2:31]C.Cl.N1C=CC=C[CH:41]=1>C1(C)C=CC=CC=1>[CH2:28]([N:25]1[N:26]=[C:16]2[C:15]3[N:27]=[CH:41][N:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:14]=3[C:23]3[C:18]([N:17]2[NH:24]1)=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:29][CH2:30][CH3:31]
Reactant: c1ccncc1
Reactant: CCCCC(OC)(OC)OC
Reactant: Nc1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Agent: Cl
Solvent: Cc1ccccc1
Product: CCCCN1N=C2c3ncn(CCOCCCc4cccnc4)c3-c3ccccc3N2N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under an atmosphere of nitrogen, N5-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine (2.48 g, 6.82 mmol) was dissolved in toluene (40 ml). Trimethyl orthovalerate (1.29 ml, 7.51 mmol) was added via syringe. A catalytic amount of pyridine hydrochloride was added to the reaction and the flask was fitted with a Dean-Stark trap. The reaction was heated to reflux and the volatiles were collected in the trap. After 4 hours, the reaction was cooled to room temperature and quenched by the addition of water (30 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×15 ml). The combined organic fractions were washed with brine (25 ml), dried (Na2SO4), filtered and concentrated in vacuo to provide a red/brown oil. The material was purified by flash column chromatography (silica gel, 2/1 to 95/5 ethyl acetate/hexane gradient) to yield 1.98 g of 2-butyl-6-[2-(3-pyridin-3-ylpropoxy)ethyl]-6H-imidazo[4,5-c]tetrazolo[1,5-a]quinoline as an orange oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(Cl)(Cl)Cl.O>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4]1
Reactant: OCC1CCCNC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCCC(CO)C1
Temperature: 10 °C
Yield: 97.9 %

Procedure:
A mixture of 3-hydroxymethyl-piperidine (0.6 mol) and Na2CO3 (130 g) in CHCl3 (600 ml) and water (600 ml) was stirred at 10° C. Ethyl chloroformate (115 g) was added dropwise (temperature was kept at 10° C.). The mixture was stirred until the temperature reached room temperature and the reaction mixture was stirred overnight. Water (500 ml) was added. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated, yielding 110 g (98%) of (±)-ethyl 3-(hydroxymethyl)-1-piperidinecarboxylate (interm. 17).
Reaction SMILES: [C:1]([O:4][CH3:5])(=[O:3])[CH3:2].CC(C)=O.C(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:33][C:32]1=[O:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:33][C@:32]1([CH2:2][C:1]([O:4][CH3:5])=[O:3])[OH:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: COC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COC(=O)C[C@]1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl acetate (0.25 mL, 3.2 mmol) was dissolved in THF (3 mL) under an atmosphere of Ar and cooled to −78° C. (acetone/dry ice). A solution of LHMDS (3.13 mL, 1M/THF) was added dropwise. After 15 minutes, a solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (5, 1.35 g, 2.5 mmol) in THF (7 mL) was added dropwise. After 3 hr, the reaction mixture was quenched with NH4Cl (aq), warmed to room temperature and extracted with EtOAc (1×). The organic layer was washed with brine (1×), dried (Na2SO4), and concentrated to a syrup (1.4 g, 92%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.15-7.31 (m, 20H), 2.26 (d, J=1.5 Hz, 1H), 4.81-4.97 (m, 4H), 4.45-4.66 (m, 4H), 3.98 (m, 1H), 3.58-3.75 (m, 7H), 3.31 (dd, J=9.6, 1.5 Hz, 1H), 2.73 (d, J=15.6 Hz, 1H), 2.30 (d, J=15.6 Hz, 1H). LC/MS tR=3.16 min, calcd for C37H40O8: 612.27, found 635.6 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[N:9]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:10]3=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:22]12([C:30](Br)=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:25][CH:24]=[CH:23]2>>[C:22]12([C:30]([N:14]3[C:10]4=[N:11][C:12]5[C:7]([C:8](=[O:21])[N:9]4[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=4)=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=5)=[O:31])[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:25][CH:24]=[CH:23]2
Reactant: O=c1c2ccc([N+](=O)[O-])cc2nc2[nH]c3ccccc3n12
Reactant: O=C(Br)C12C=CCC1CCC2
Product: O=C(n1c2ccccc2n2c(=O)c3ccc([N+](=O)[O-])cc3nc12)C12C=CCC1CCC2

Procedure:
6-(Bicyclo[3.3.0]octenoyl)-3-nitrobenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 3-nitrobenzimidazo[2,1-b]-quinazolin-12(6H)one and bicyclo[3.3.0]octenoyl bromide.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[CH3:12][C:13]1([CH3:25])[CH2:19][NH:18][C:17](=O)[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[O:14]1>>[Cl:7][C:17]1[C:16]2[CH:21]=[CH:22][CH:23]=[CH:24][C:15]=2[O:14][C:13]([CH3:25])([CH3:12])[CH2:19][N:18]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1(C)CNC(=O)c2ccccc2O1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CN=C(Cl)c2ccccc2O1
Temperature: 25 °C
Yield: 112.8 %

Procedure:
After adding phosphorous oxychloride (5 mL) and phosphorous pentachloride (0.65 g, 3.13 mmol) to 2,2-dimethyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.60 g, 3.13 mmol) (refer to the aforementioned Non-Patent Document 3 for a description of the synthesis method) at room temperature, the mixture was refluxed while heating for 5.5 hours. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure and the residue was poured over crushed ice. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layer was washed twice with “saturated aqueous sodium bicarbonate solution (30 mL)+H2O (20 mL) and then with brine (30 mL) followed by drying with magnesium sulfate. After filtering, the solvent was distilled off under reduced pressure to obtain 0.74 g of 5-chloro-2,2-dimethyl-2,3-dihydro-benzo[f][1,4]oxazepine in the form of a brown oily substance. This substance was used in the next reaction without purifying further.
Reaction SMILES: CCO.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[O:9][CH2:10][C:11](=O)[C:12]#[C:13][C@@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1C(OC(C)(C)C)=O.Cl.[NH2:33][OH:34].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[O:9][CH2:10][C:11]1[CH:12]=[C:13]([C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[O:34][N:33]=1
Reactant: NO
Reactant: COc1ccc(OCC(=O)C#C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1OC
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(OCc2cc([C@@H]3CCCN3)on2)cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 107 %

Procedure:
To an EtOH (10 mL) solution of the compound (390 mg) obtained in Example 14-(2), hydroxylamine hydrochloride (139 mg) was added and the mixture was heated under reflux for 20 hours. The reaction mixture was concentrated to give a brown oil, to which CHCl3 (1.0 mL) and TFA (5.0 mL) were added, followed by stirring at room temperature for 21 hours. After concentrating the reaction mixture, saturated aqueous sodium bicarbonate (50 mL) was added and the organic layer extracted with CHCl3 (50 mL×2) was dried (Na2SO4), filtered and concentrated to give the titled compound (326 mg, brown oil) as a mixture with impurities.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1.C(N(CC)CC)C>O>[C:14]([NH:13][CH2:12][CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([NH:2][C:25](=[O:26])[CH2:24][C:23](=[O:27])[CH3:22])[CH:4]=1)(=[O:16])[CH3:15]
Reactant: C=C1CC(=O)O1
Reactant: COc1ccc(CCNC(C)=O)cc1N
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(C)=O)cc1NC(=O)CC(C)=O
Temperature: 82.5 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
N-[-2-(3-amino-4-methoxyphenyl)ethyl]acetamide hydrochloride (19 g) was mixed with 40 mL N,N-dimethylformamide and 18 g of diketene followed by slow addition of 3 mL of triethylamine. The mixture was stirred at 80-85° C. for 30 minutes and then poured into 300 mL of water. The aqueous solution was extracted with chloroform (2×200 mL) and the solvent was removed by rotary evaporation to yield 21.9 g (96.5%) of N-[5-(2-acetylaminoethyl)-2-methoxyphenyl]-3-oxo-butyramide as a light yellow oil. 1HNMR (DMSO-d6) spectrum was consistent with the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[C:29]([F:53])=[CH:30][C:31]([Cl:52])=[C:32]([CH:51]=1)[O:33][C:34]1[CH:48]=[CH:47][C:37]2[N:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[S:40][C:36]=2[C:35]=1[C:49]#[N:50]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:51]=[C:32]([O:33][C:34]2[CH:48]=[CH:47][C:37]3[N:38]=[C:39]([NH:41][C:42]([CH:44]4[CH2:46][CH2:45]4)=[O:43])[S:40][C:36]=3[C:35]=2[C:49]#[N:50])[C:31]([Cl:52])=[CH:30][C:29]=1[F:53])=[O:6]
Reactant: N#Cc1c(Oc2cc(N)c(F)cc2Cl)ccc2nc(NC(=O)C3CC3)sc12
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c(Cl)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (74 mg, 0.330 mmol) in tetrahydrofuran (1 mL) were added oxalyl chloride (35 μL, 0.408 mmol) and N,N-dimethylformamide (5 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(5-Amino-2-chloro-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (90 mg, 0.223 mmol) produced in Example 23(vi) was added to the solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (7 mL) and saturated brine (7 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80→80/20), and the obtained solution was concentrated under reduced pressure to give the title compound (120 mg, 88%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[S:5][C:6]=1[CH:7]([OH:10])[CH2:8][CH3:9].[C:14]([O-])([O-])=O.[K+].[K+].IC.O>CN(C)C=O>[CH3:14][O:12][C:11]([C:4]1[S:5][C:6]([CH:7]([OH:10])[CH2:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CCC(O)c1sc(C(=O)O)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCC(O)c1sc(C(=O)OC)cc1Cl
Reaction time: 8 h
Yield: 31.4 %

Procedure:
A solution of crude 4-chloro-5-(1-hydroxy-propyl)-thiophene-2-carboxylic acid (0.262 g) in dimethylformamide (6.0 mL) is treated with K2CO3 (0.502 g, 3.63 mmol) and iodomethane (0.17 mL, 2.73 mmol) and stirred overnight. The reaction mixture is then poured into H2O (15 mL) and extracted with EtOAc (3×10 mL). Combined organic extracts are washed with brine (1×), dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 50% EtOAc to provide 4-chloro-5-(1-hydroxy-propyl)-thiophene-2-carboxylic acid methyl ester (87.6 mg, 15%-2 steps) as a yellow syrup. MS (ES): 216.9 [M+H]+.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3].[CH3:28]N1CCOCC1.[N+](=C)=[N-].[BrH:38]>>[NH:1]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([CH2:28][Br:38])=[O:17])=[O:12])[CH:8]([CH3:9])[CH3:10])=[O:5])[CH3:3]
Reactant: CN1CCOCC1
Reactant: Br
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: C=[N+]=[N-]
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)CBr

Procedure:
12 (0.88 g, 2.28 mmol) was treated as described for 13, using CAIBE (2.28 mmol, 0.37 ml), NMM (2.28 mmol, 0.31 ml), diazomethane (14.3 mmol in 15 ml ether) HBr/glacial acetic acid (33%): 4.24 mmol, 1.04 ml.
Reaction SMILES: [NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([CH2:10][C:11](=[O:30])[N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:14][CH2:13]2)[CH:8]=O)=[CH:4][C:3]=1[Cl:37].[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[NH:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50](C(OC(C)(C)C)=O)[CH2:49][CH2:48]1.C(O)(C(F)(F)F)=O>CN(C=O)C.ClCCl>[NH2:1][C:2]1[C:32]([C:33]([F:34])([F:36])[F:35])=[CH:31][C:5]([CH2:6][CH:7]([C:8]2[N:45]([CH2:46][CH:47]3[CH2:48][CH2:49][NH:50][CH2:51][CH2:52]3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=3[N:38]=2)[CH2:10][C:11]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:24][CH2:23][C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[NH:20][C:19]3=[O:29])[CH2:16][CH2:17]2)=[O:30])=[CH:4][C:3]=1[Cl:37]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccccc2N)CC1
Reactant: Nc1c(Cl)cc(CC(C=O)CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)cc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)c2nc3ccccc3n2CC2CCNCC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 537 mg (1.000 mmol) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butyraldehyde (Intermediate product 36) in 10 mL DMF was added tert. butyl 4-[(2-amino-phenylamino)-methyl]-piperidin-1-carboxylate (Intermediate product 34) and the mixture was stirred for 16 hours in an atmosphere of air at RT. The reaction mixture was poured onto ice water, the precipitate formed was filtered off, washed with water and dried i. vac. (Yield: 790 mg, 96% of theory). 1 mL of TFA was added to a solution of 580 mg (0.705 mmol) of the crude product in 10 mL dichloromethane and the mixture was stirred for 16 hours at RT. The reaction mixture was diluted with dichloromethane, the org. phase was washed with sat. aqueous sodium bicarbonate solution, dried over sodium sulphate and evaporated i. vac. The residue was dissolved in 3.5 mL DMF and purified by HPLC-MS (Zorbax Bonus C18 amide-phase 5 μm, gradient 0.15% formic acidin water/acetonitrile 10/90→90/10 v/v) and then lyophilised.